Primary hyperparathyroidism is the one of the most common endocrine disorders. Primary hyperparathyroidism results from parathyroid adenomas while secondary hyperparathyroidism results from parathyroid gland hyperplasia in the setting of renal disease. Both conditions are associated with decreased expression of the Ca2+ sensing receptor (CaSR) which is required to suppress parathyroid hormone (PTH) secretion in the setting of hypercalcemia. Understanding the molecular mechanisms that regulate PTH secretion downstream of CaSR is critical for the discovery of new therapeutics to treat hyperparathyroidism and its associated morbidity. Here we show for the first time that Tprc1-null mice develop primary hyperparathyroidism, hypercalcemia, and low urinary calcium excretion mimicking the human disease Familial Hypocalciuric Hypercalcemia (FHH). FHH is a form of primary hypeparathyroidism and caused by inactivating mutations in CASR, GNA11 and AP2S1 encoding CaSR, the ?11 subunit of the guanine nucleotide-binding protein, and the ?1 subunit of the AP2 clathrin-associated adaptor complex mediating recycling of cell surface receptors and channels, respectively. Thus, we tested whether TRCP1 function is directly linked to CaSR signaling. Biochemical, functional, and cell biological experiments in vitro show that TRPC1 is activated by CaSR involving the action of G?11. We also show that TRPC1 physically interacts with AP2?1. These data lead us to the hypothesis that TRPC1 is required for normal suppression of PTH secretion in the parathyroid gland by acting downstream of CaSR via G?11. The interaction of TRPC1 with AP2?1 increases the availability of TRPC1 for CaSR-induced signaling by accelerating recycling of inactivated TRPC1. In Aim 1, we will employ cell biological approaches to define the mechanism by which TRPC1 mediates CaSR-induced Ca2+ signaling and the role of G?11 and AP2?1 in this signaling pathway in cells derived from the parathyroid gland. In specific Aim 2, we will determine whether TRPC1 functions downstream of CaSR and G?11 in vivo, by asking whether compound mice lacking Trpc1 and Casr or Gn?11/Gn?q genes in their parathyroid glands show more severe FHH-like phenotypes than phenotypes elicited by single gene deletions. Understanding the pathways that regulate PTH secretion could have a high impact on designing new and more effective and specific approaches to treat patients with primary as well as secondary hyperparathyroidism.